The Endocannabinoid System: A New Perspective
for Cardiometabolic Risk Control
Emilio Antonio Francischetti and Virginia Genelhu de Abreu
Hypertension Clinic, Laboratory of Clinical and Experimental Pathophysiology, Rio de Janeiro State University - Rio de Janeiro, RJ - Brazil
Mailing address: emilio Antonio Francischetti •
The prevalence of many cardiovascular risk factors has been significantly reduced in the last forty years1. Therapeutic advance gained from lipid-lowering agents, anti-hypertensive drugs, and anti-diabetic oral agents have acted as invaluable tools to reduce the heavy burden imposed by cardiovascular and metabolic risk factors on public health. Despite this evidence, cardiovascular diseases still remain a major cause of death in many countries in the Western World - whether due to inappropriate control of diseases such as diabetes mellitus and hypertension, and the smoking habit1, or by the emergence of new risk factors such as abdominal obesity2,reduced levels of HDL-C, hypertriglyceridemia and higher proportion of small and dense LDL particles3, all recognized to act as contributory elements for cardiovascular risk as a whole.
Although clinical trials have demonstrated significant reduction in the number of events by the use of highly effective therapeutic regimens, a major residual risk still remains, leaving a considerable number of treated patients vulnerable to cardiovascular and metabolic morbidity4-6. This is particularly alarming for individuals reporting multiple risk factors.
Obesity – especially visceral adiposity – is an ongoing pandemic affecting the populations of both developed and developing countries, as Brazil7,8, in a similar way. In our days, visceral adipose tissue is seen as a potentially diabetogenic, pro-hypertensive, pro-inflammatory, and pro-atherosclerosis endocrine organ9. Changes in the expression and secretion of adipocytokines and inflammatory mediators explain the association of abdominal adiposity to insulin resistance, atherogenic dyslipidemia, and hypertension. These factors are included as syndrome components, in the different definitions, of Metabolic Syndrome — ATP III11, World Health
Organization12 and International Diabetes Federation (IDF)13. Recent studies have identified the molecular basis, the neuronal circuits, and the metabolic pathways involved in food intake regulation. A considerable number of neuropeptides has been characterized in distinctive hypothalamic nuclei as interacting with signals originated at peripheral organs, which suggests that there is a complex network participating not only in appetite and satiety control, but also in energy balance modulation and body constitution14.
The endocannabinoid system is an endogenous signaling system with physiological action on energy homeostasis regulation as well as on lipids and carbo hydrates metabolism15. Endocannabinoid system hyperactivation not only results in body weight increase15 but can also induces dyslipidemic and dysglycemic phenotypes16. A number of clinical and experimental studies have shown that pharmacological
intervention in the system has proven to be a promising therapeutic perspective to control obesity, dyslipidemia, insulin resistance and atherosclerosis17,18.
The endocannabinoid system
History
Cannabis Sativa (marijuana) is the most widely consumed illegal drug in the world as of the 1960’s19. Having been cultivated for over five thousand years for the fibers it provides for materials manufacturing process, Cannabis had been prescribed by the Chinese as from 2600 BC to treat cramps, rheumatic and menstrual pain20. However, not until 1964 was
its active ingredient ∆9-tetrahydrocannabinol(THC) isolated and its chemical structure characterized21. In our days, a considerable number of Cannabis Sativa analogues have been prescribed as antiemetic and appetite stimulants to oncology patients on chemotherapy. Dronabinol – a THC synthetic compound – was approved by the FDA over fifteen years ago as ancillary management for advanced stages of AIDS and cancer patients that develop anorexia and cachexia22-24.
The first cannabinoid receptor was identified25 in 1988. In 1993, that receptor was called CB1, after that same year a second receptor had been characterized and named CB226. Both receptors are coupled to Gi/o proteins and belong to a wide and diverse family of proteins coupled to the cellular membrane. Tissue distribution in those structures explains most of the psychotropic effects of THC accounted to CB127 receptors. The effects of CB2 peripheral receptors are more closely associated to immune response28.
The first cannabinoid receptors endogenous ligands – the endocannabinoids – were isolated in 199229.Presently, anandamide (N-arachidonoyl ethanolamine) and 2-araquido-noil glycerol (2-AG) are the most extensively studied among all endogenous cannabinoids. “Ananda” comes from Sanscrit and means serene happiness or eternal happiness20. Both endocannabinoids are CB1 and CB2 receptors agonists. 2-AG cell and tissue levels are higher than those of anandamide as a result of their higher involvement in different metabolic pathways. Cannabinoid receptors, endocannabinoids, as well as the enzymes that catalyze their biosynthesis and degradation constitute the endocannabinoid system.
CB1 and CB2 Receptors
inhibit) and MAPK (Mitogen-Activated Protein Kinases) – which they stimulate. As for CB1 receptors, specifically, modulation is carried out on voltage activated Ca2+ channels (which they inhibit) and K+ channels (which they stimulate)30. The primary function of those receptors is the transduction of extra cellular stimuli in intracellular signals.
Among the G Protein-coupled membrane receptors, the CB1 are the more abundant so far identified in the central nervous system, although they are also found in peripheral nervous system31.Through their receptors, major actions can be seen by endogenous cannabinoids on central nervous system, such as cognitive and emotional function regulation at neuronal circuits in the cortex, in the hippocampus and amygdala, and in boosting substances effects that lead to chemical dependence in the mesolimbic system: cocaine32, heroin33, anphetamine34 and alcohol35.
Some studies have shown the important role played by the endocannabinoid system in modulating nicotine dependence. In CB1-/- animals, nicotine rewarding effects are abolished36 and the administration of a selective CB1 antagonist – rimonabant – reduces their search for the alkaloid37.
CB2 receptors are located in structures associated to immune system and hematopoiesis modulation. Stimulation of those structures by ∆9-tetrahydrocannabinol results in an immunosuppressant phenotype38.
Formation and inactivation of endocannabinoids. Retrograde Neurotransmission Process
Most endocannabinoids identified so far are by-products of PUFAs –long chain polyunsaturated fatty acids, especifically arachidonic acid (Figure 1). Therefore, anandamide and
Fig. 1 - Most endocannabinoids are long-chain polyunsaturaded fatty acids by-products. Anandamide and 2-arachidonoyl glycerol (2-AG) are produced from the remodeling of phospholipids through pathways that use NAPE-PLD (N-acylphosphatidylethanolamine-seletive phospholipase D) and DAG (Diacylglycerol) lipase synthesis enzymes. They are rapidly metabolized and hydrolized by FAAH (Fatty Acid Amide Hydrolase) and MAG L (Monoacyl Gycerol Lipase) enzymes.
Endocannabinoids have local action and are produced on demand. Adapted from: Di Marzo V et al.52
Endocannabinoids Formation
and Inactivation
N H
O O
P O
O-O
O-R2
R1O
O O
CH O-R3
OH
N H
OH O
O O
CH OH
OH
NAPE-PLD DAG Lipase
Phospholipids-derived Precursors
Endocannabinoids
2-Arachidonoyl glycerol
Anandamide
Phospholipids remodeling
O
OH
H2N OH HO CH
OH
OH
FAAH MAG Lipase
2-AG are formed by phospholipid independent pathways; the synthesis enzymes are N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAG Lipase), respectively39,40.
Although most endocannabinoids act under demand or need, in response both to physiological (neuronal depolarization) and pathological15 stimuli, evidence has shown that their primary activation takes place in some areas in the brain where energy balance is controlled, thus suggesting an ongoing tonus that favors energy intake and storage41.
Both anandamide and 2-AG have their action interrupted by a neuronal reuptake process, followed by their metabolism. This stage seems to take place by mere diffusion and/or through a process facilitated by a carrier protein. Both endocannabinoids are quickly metabolized and hydrolized by FAAH (Fatty Acid Amide Hydrolase)and MAG lipase (Monoacyl Glycerol), respectively, in inactive compounds16,42.
The multiple functions of the
endocannabinoid system
Fig. 2 - 2-AG levels measured directly at the hypothalamus and in limbic
forebrain show different values in food-deprived animals, whose levels are significantly higher when compared to animals being fed. No change was
observed in satiated animals. Adapted from: Kirkham TC et al.55
2
-ar
ac
hi
do
no
yl
g
ly
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(n
m
ol
/g
ti
ss
ue
w
ei
gh
t)
0
5
10
15
20
Control Eating Satiated Deprived
Hypothalamus Limbig forebrain
*
* *p<0.05
**p<0.01 **
**
relaxation9; 7) antitumoral activity50; 8) neuroprotection against trauma and hypoxia conditions51; 9) food intake modulation due to its effects on the release of peptides and hypothalamic hormones and to their regulation by steroids31. All of those pleiotropic effects have been summarized by Di Marzoand cols52in one statement: “The endocannabinoid system reduces the feeling of pain; controls movement, memory, sleep, and appetite; and is protective.”
The tonic activation of cardiac and vascular CB1 receptors seems to limit blood pressure increase. Recently, Kunos and cols53 have observed that when spontaneously hypertensive rats (SHR) were treated with an anandamide degradation inhibitor their hypertension condition was controlled. Such effect was reversed by the administration of CB1 antagonists. In addition to reducing SHR blood pressure, endocannabinoids inactivation blocking concurrently reduced left ventricle contractile performance, although the same parameters were not shown to have been affected in normal animals53.
Another extremely intriguing observation – this time in regard to CB2 receptors function – is that their immunosuppressant properties would have a beneficial, protective effect on the inflammatory milieu of the atherosclerotic lesions. While working with apoliprotein E receptors knock-out mice fed with a cholesterol-rich diet, Stefens and cols54 have observed significant regression of the atherogenic plaques that are peculiar to that model when the animals were treated with small oral doses of THC. A plausible explanation would be that CB2 receptors expressed in the atherosclerotic lesions, but not in normal arteries, would be activated by THC.
Food Intake Regulation by Endocannabinoids
Central effects of CB1 receptors activation are ultimately reflected on energy balance modulation and appetite control. A body of evidence from experimental studies with obese animals (ob/ob and db/db mice and obese Zuker rats) and normal murine models has shown that: 1) the activation of CB1 receptors by endogenous cannabinoids or THC and the injection of endocannabinoid directly in the hypothalamus or in the mesolimbic region stimulate food intake55,56; 2) in contrast, animals whose CB1 receptors genes had been suppressed (CB1-/-) have lower food intake and exhibit a slim phenotype resistant to diet-induced body weight increase57; 3) under normal conditions, the intake of nutrients reduces endocannabinoids levels in the hypothalamus and in limbic forebrain, while fasting has the opposite effect, significantly increasing them55.
Figure 2 shows that food deprived rats have consistently increased 2-AG tissue levels both in the limbic forebrain and in hypothalamus, which are areas strongly associated to motivation and the pleasure of eating55. The 2-AG levels are shown to decrease when animals are being fed.
In another experiment, when anandamide was administered to mice, food intake increased 44% and was shown to be significantly associated to hypothalamic concentrations of norepinephrine, dopamine, and serotonin58.
In 2003, Cota and cols38 demonstrated that CB
1-/- animals – although slimmer – did not report any change in their locomotor activity, body temperature or energy expenditure when compared to wild akin. Such data show that the decrease
in central orexigenic stimulus, as a result of the absence of the CB1 receptor, explains the differences between those animals rather than the changes in their locomotor activity or their energy expenditure.
The administration of rimonabant – the first CB1 selective antagonist, described in 1994 by Rinaldi-Carmona and cols59 – to diet induced obese mice, led to sustained body weight reduction when compared to control animals. CB1 blocker persistent effects on body weight reduction in these animals – in contrast with transitory decrease in food intake – suggest that other mechanisms would contribute for rimonabant long-lasting effects in addition to caloric intake60 (Figure 3).
These data suggest that the endocannabinoid system controls energy intake at two levels. Firstly, by tonically accentuating and incentivating motivation for food search and intake, possibly from interacting with the mesolimbic pathways (nucleus accumbens) involved in reward mechanisms. Secondly, the system is activated on demand in the hypothalamus – after a short period of food deprivation – to then transiently modulate the levels and/or the action of other orexigenic and anorexigenic mediators for the purpose of appetite induction. The assumption of a dual action in the mesolimbic and hypothalamic regions has been proven by the demonstration that food intake in rodents42 is stimulated when endocannabinoids are injected in those encephalic areas.
In the hypothalamus, endocannabinoid levels changes are inversely correlated to leptin plasma concentrations, the hormone secreted by the adipocyte which plays a key role in food intake and energy expenditure regulation. Leptin reduces endocannabinoid levels in the hypothalamus, similarly to what it does to other orexigenic mediators. Additionally, obese mice genetically defficient in leptin signalling pathways exhibit increased concentrations of endocannabinoids in the hypothalamus57.
Co-expression of CB1 receptors with anorexigenic and orexigenic mediators
Fig. 3 - Effects of rimonabant on food intake (to the left) and obese mice weight (to the right) after fat rich diet intake. It should be pointed out that sustained effects
on drug induced weight loss contrast with lower intake as observed only in the first treatment week. Adapted from: Ravinet Trillou C et al.60 Daily Average of Food Intake
-Fat-rich Diet (FRD)
Vehicle 3 mg/kg rimonabant 10 mg/kg rimonabant Treatment Time (days)
Da
ily
in
ta
ke
(k
ca
l)
0
5
10
15
20
Days
0 8 16 24 32 40
W
ei
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t(g
)
26 28 30 32 34 36 38 40 42
0-8
** **
9-16 17-24 25-32 33-40
FRD + 3 mg rimonabantFRD + Vehicle
FRD + 10 mg rimonabant
* * ** ** **
**
** ** ** **
(-18 %)
Standard diet/Vehicle Standard diet/10 mg
have shown that CB1 receptors are co-expressed: 1) at the paraventricular nucleus with the anorexigenic mediator CRH (Corticotropin Release Hormone)61, where the endocannabinoids act in a retrograde way reducing the glutamatergic transmission of pre-synaptic neurons, thus attenuating CRH release62; 2) at hypothalamus lateral nucleus with orexigenic mediator MCH (Melanin-ConcentratingHormone)61; 3) at the arcuate nucleus with CART (Cocaine Amphetamine Regulated Transcript)61 expressing cells; and 4) at ventromedial hypothalamus with prepro-orexin61. The genetic deletion of CB
1 receptors increases CRH expression, thus reflecting the tonic inhibition of that mediator by endocannabinoids63.
A positive and direct correlation can be observed between endocannabinoid system tonus and ghrelin circulating levels after food deprivation. That peptide – secreted by the digestive tract – acts locally and interacts with endocannabinoids at vagal afferent terminations, thus increasing food intake. Those effects are blocked by rimonabant64.
As for the mesolimbic system, there is evidence showing that endocannabinoids would increase the yearning for food while inducing higher dopamine release at the nucleus accumbens or by synergic action with opioids through yet unkonwn mechanisms65.
Another important aspect in satiety control is the relationship between endocannabinoid system and vagal terminations connecting the gastrointestinal tract to the medulla and brainstem nuclei area. Endocannabinoids reduce satiety through their action on the vagus. Such effects may be reversed by the destruction of capsaicin-sensitive vagal terminations that modulate the effects of cholecystokinin on satiety66. On the other hand, cholecystokinin inhibits the expression of CB1 receptors through vagal afferent neurons67.
Those data suggest that reduced endocannabinoid activity may mediate the induction of satiety activity by cholecystokinin. As a counterpart, fasting overcomes satiety by stimulating the secretion of endocannabinoids in the small intestine, thus
releasing vagal CB1 from cholecystokinin inhibition.
Peripheral Effects of CB1 Receptors Activation
The endocannabinoid system plays an effective role in lipogenesis modulation. When stimulated, CB1 receptors increase lipoprotein lipase expression and reduce adiponectin44. As a counterpart, CB1 receptor blocking has resulted in increased expression of adiponectin – both in vitro and in vivo. Adiponectin has a crucial role in reducing the expression of enzymes involved in lipogenesis69,70, with potential major role in atherogenic dyslipidemia and disglycemia. Additionally, the activation of CB1 receptors in hepatocytes is translated into increased de novo synthesis of fatty acids by these cells, as a result of the higher genic expression of the lipogenic transcription factor SREBP-1c (Sterol Regulatory
Element-Binding Protein 1c), as well as of associated enzymes: FAS (Fatty-Acid Synthase) and Acyl-CoA C1 (Acetyl-CoA
Carboxilase-1). Contrarily, CB1-/- mice are resistant to those changes and to the development of hepatic steatosis71.
As for glycemic homeostasis, CB1-/- mice shows lower glucose levels after insulin intraperitoneal administration when feeding a fat-rich diet, as compared with wild animals72. They also exhibited a reduction in leptin and insulin plasma concentrations, thus suggesting higher sensitivity to these two hormones.
It has recently been demonstrated that rimonabant increases oxygen consumption and glucose uptake by the solear muscle of ob/ob73 mice, thus showing the favorable effects of the drug on thermogenesis and insulin sensitivity.
The pathophysiologic consequences
of endocannabinoid system hyperactivity
increasing lipogenesis and reducing energy expenditure42. This is consistent with the concept that increased levels of endocannabionoids – inevitable in the presence of stimuli associated to stress – would act as a strategy in helping superior organisms for the purpose of homeostasis retrieval.
As a counterpart, results from pre-clinical and clinical trials have clearly indicated that the system also contributes for the modulation of conditions accompanied by hyperphagia and adipose mass accumulation, and that its pharmacological blocking would reverse this scenario. Sustained hyperactivity of the system in tissues that control energy balance would, therefore, play a key role not only in the development of obesity but in the emergence of the consortium of cardiometabolic risk factors15 (Figure 4).
The question that must be asked is: Which causal factors would be involved in the changes from a system that acts “on demand” to a sustained hyperactivity system? Apparently, such hyperactivity would be associated to fat-rich diets that make polyunsaturated fatty acids available for the biosynthesis of the endocannabinoids42. Additionally, obese rats’ adipocyte has shown higher expression of CB1 receptor when compared to the adipocyte of slim rats or immature adipocytes70. A fat-rich diet also results in higher anandamide synthesis by the hepatocytes with higher expression of CB1 receptors71
. Against to this scenario, openly pro-orexigenic, significant resistance to leptin anoretic actions would take place57.
A missense polymorphism in homozygote genotype FAAH 385 A/A has recently been identified in overweight and obese individuals, showing potentially inadequate functioning of one of the key enzymes in endocannabinoids74 degradation pathways, which would be an additional explanation for system hyperactivity.
Indeed, the assumption of endocannabinoid system
Fig. 4 - Repercussions of endocannabinoid system hyperactivity at central sites responsible for hunger and motivation for food, as well as in peripheral tissues. Sustained hyperactivity contributes for the development of overweight and the emergence of cardiometabolic risks that are aggregated under the metabolic syndrome
denomination. Adapted from: Di Marzo V, Matias I 15, Pagotto U et al.16
Adipose
tissue Liver GI Tract Muscle
Food intake Fat storage
Insulin resistance
HDL-C
TG
Glucose Uptake Adiponectin Hypothalamus:
hunger Nucleus motivation to eataccumbens:
Brain Peripheral tissues
Central and Peripheral Effects of
Endocannabinoid System Hyperactivity
sustained hyperactivity in certain circumstances has been the
leitmotiv to sponsor the indication of CB1 selective antagonists for the management of obesity and its consequences.
Effects of CB
1receptors selective
blocking on cardiovascular risk factors.
The RIO (
Rimonabant In Obesity
) Program
The blocking of CB1 receptors with selective antagonists, as rimonabant, seems to be a promising perspective for the reduction of cardiovascular diseases that persist even after therapeutic regimens, considered highly effective, have been unfavorable.
Rimonabant pharmacokinetic studies have shown that the drug has rapid oral absorption, with a terminal half-life of 9 days in healthy individuals, and of 16 days in obese individuals. It is metabolized by the CYP3A and amidohydrolase, and eliminated by biliary pathways, with insignificant renal excretion. No rimonabant dosage adjustments are required for mild to moderate renal and hepatic failure patients. Co-administration of rimonabant with food or orlistat showed to be of minimal impact on the drug pharmacokinetics75.
Dyslipidemia rate ranged from 55.7% in the RIO-Diabetes to 100% in the RIO-Lipids. Metabolic syndrome rate ranged from 34.7% in the North America to 79.3% in the RIO-Diabetes. Hypertension percentage ranged from 61.2% in the RIO-Diabetes to 27.2% in the RIO-Lipids. The trials were carried out in the United States, Canada and Europe.
RIO-Lipids trial included 1,033 patients who were overweight or obese, and had non-treated dyslipidemia. Diabetics were excluded. The trial was one-year long17. The RIO-Europe trial included 1,507 overweight or obese individuals, with or without comorbidities. Diabetics were also excluded in this two-year long76 trial. The RIO-North America trial included 3,040 obese or overweight individuals, with or without associated comorbidities. The study also excluded diabetics and had two phases: the first was 12-month long; the second, with patients who had been on rimonabant and randomized to an arm that used placebo and another that kept the same dosing for rimonabant18. The RIO-Diabetes randomized 1,047 patients – all of them overweight, obese, and with type 2 diabetes. This trial last one-year77.
Significant waist circumference (-8,5cm) and body weight (-8,6kg) reduction could be seen after one year in the three studies that were published, with rimonabant, 20mg/ day (Figure 5). Prevention against weight and abdominal circumference regain was evaluated in RIO-North America patients, who were re-randomized to the 20mg/20mg rimonabant arm.
As for rimonabant effect on cardiometabolic risk factors, the following results were observed:
1) HDL-C, triglycerides, small and dense LDL, and LDL-C levels
Rio-Europe reported significant changes in triglycerides (-6,8%) and HDL-C (22.3%) concentrations after one year under treatment (vs placebo) in the group on 20mg rimonabant. The changes in those two parameters were very similar in RIO-Lipids and were maintained after two years on the drug in RIO-North America. Rimonabant had no appreciable effect on cholesterol and LDL-C levels in any of the three studies. In RIO-Lipids, there was a significant reduction in the proportion of LDL small and dense particles, in the Rimonabant 20 mg group (Figure 6), when compared to placebo. Logistic regression models and/ or ANCOVA using body weight loss as covariable, showed that after 20mg of rimonabant, both HDL-C and triglycerides reported changes partially independent of weight loss (Figure 7).
2) Changes in glycemic parameters.
An analysis of the three clinical trials that were published characterized a subgroup of pre-diabetic patients (n=1,290) whose glucose fasting levels ranged between equal to or higher than 100mg/dl and lower than 126mg/dl. The results showed that 46.5% of pre-diabetic patients who were administered 20mg/day of rimonabant for one year had fasting glucose levels back to normal values (under 100mg/dl).
As for drug effects on glycosylated hemoglobin values, RIO-Diabetes showed that 43% of patients on 20mg of rimonabant had this parameter reversed to normal values (under 6.5% after one year of treatment, when compared to the placebo group, where that change was reported for 21% of patients).
Significant improvement was also reported in insulin fasting concentration, as well as in insulin resistance calculated by HOMA, when results were compared with the placebo group. After one year of treatment with placebo, and 5mg and 20mg/ day of rimonabant, metabolic syndrome prevalence in those groups was 48.1%, 46.4% and 32.3% (p=0.30 and p<0.001
vs placebo, respectively).
3) RIO-Lipids showed that adinopectin levels increased by 57.7% with the administration of 20mg of rimonabant. That difference was significant when compared to the placebo group (Figure 8). It is important to point out that over 50% of such increase happened irrespective of body weight loss. Additionally, adiponectin levels had a positive and significant correlation with changes in HDL-C and Apo-A1. The same trial showed that leptin levels significantly decreased with the administration of rimonabant - both at 5mg and 20mg regime. Plasma concentrations of C-reactive protein were significantly reduced in the rimonabant group, thus showing favorable drug interference in that inflammatory marker (Figure 6). Systolic and diastolic pressure were significantly reduced (-2.1mmHg and -1.7mmHg, respectively). Hypertensive patients showed a higher reduction.
4) Drug primary efficacy analysis was applied to the ITT (Intention-To-Treat) population and based on LOCF (Last Observation Carried Forward). As general, 20mg dosing of rimonabant was well tolerated, and adverse effects – mild to moderate – were mostly limited to depression episodes [2.9% vs 0.6% (placebo)], anxiety [1.7% vs 0.6% (placebo)] and nausea [1.2% vs 0% (placebo)]. Serious adverse effects that led to study discontinuation were reported by 5.2%, 4.0% and 2.3% among patients who were on 20mg, 5mg and pla-cebo, respectively17, for one year. Patients receiving the same treatment for two years reported comparable discontinuation rate due to adverse effects (4% placebo, 6.3% 5mg, 4.2% 20mg), thus suggesting that they occur early, and that 5mg and 20mg of rimonabant exhibit tolerability and safety profile similar to placebo18.
5) Based on RIO-Program, no relevant interaction was reported between anti- hypertensive agents, vastatins, oral anti-diabetic drugs, fibrates and rimonabant17,18,76,77.
In addition to the clinical trials included in the RIO-Program, other studies are being carried out to investigate whether the improvement in cardiometabolic risk profile by the administration of rimonabant is translated by changes in coronary atherosclerotic plaque volume, as measured by intravascular ultrasound (STRADIVARIUS Study)79. The possible benefits of rimonabant on fatal and non-fatal outcomes, as a result of acute myocardial infarction episodes and stroke, are being evaluated in a prospective, randomized, and controlled trial (CRESCENDO Study), currently in patient recruiting phase.
Fig. 5 - Effects of rimonabant (20 mg/day) on body weight (A) and waist circumference (B) after one year of treatment. Data show patients who have completed the three studies: RIO-Lipids, RIO-North America and RIO-Europe. Adapted from: Després JP et al 17, Pi-Sunyer FX et al 18, Van Gaal LF et al. 75
-10 -8 -6 -4 -2 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 LOCF
Body weight change (kg)
Weeks
-8.6 kg* -2.8 kg*
-10 -8 -6 -4 -2 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 LOCF
Waist circumference change (cm)
Weeks
-8.5 cm* -3.9 cm*
RIO-Europe
Placebo
R 20 mg*
RIO-Lipids
Placebo
R 20 mg*
RIO-North America
Placebo
R 20 mg*
A B
Fig. 6 - In the RIO-Lipids, LDL particle distribution showed that the larger ones were found in the group that received 20mg of rimonabant (A), when compared to placebo. This resulted in significant 4.7% reduction in the proportion of small and dense LDL particles (B). Significant reduction was also shown (0.6 mg/L) in ultrasensitive CRP (C). P values refer to the differences between the 20mg rimonabant group vs placebo group. Adapted from: Després JP et al.17
20 22 24 26 28 30 32 34
20 25 30 35 40 45
Small LDL particles %
p=0.002
p<0.001
Large LDL particles %
Proportion of small and dense, LDL particles Proportion of large LDL particles
Placebo Rimonabant 20 mg Placebo Rimonabant
20 mg
1 year
Baseline ITT, LOCF
26.2 29.5
25.8 24.4 40.2
35.1
40.0 41.2
ITT, LOCF
0 1 2 3 4 5
CRP Levels (mg/L)
* Valoresacima de 10mg/L foram excluídos.
Placebo Rimonabant
20 mg
p=0.007
3.6
3.2 3.7
↓27%
ITT, LOCF
A B
C
* Data show patients that completed the 3 studies p<0.001.
References
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4. Heart Protection Study Collaborative Group. MRC; BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo controlled trial. Lancet 2002;360:7-22.
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in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
6. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifatorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393.
7. Instituto Brasileiro de Geografia e Estatística – IBGE. Pesquisa de orçamentos familiares 2002-2003. Rio de Janeiro 2004, 80p.
8. WHO MONICA. Project Geographical variation in the major risk factors of coronary heart disease in men and women aged 35-64years. World Health Statistics Quaterly 1988;41:115-140.
9. Barroso SG; Abreu VGA, Francischetti EA. A participação do tecido adiposo visceral na gênese da hipertensão e doença cardiovascular aterogênica. Um Data analysis of these clinical trials shows that pharmacological intervention on endocannabinoid system is not only an innovative alternative, but also very promising for the treatment of cardiometabolic risk factors associated to abdominal obesity, and possibly a truly potential tool for the prevention of atherosclerosis and its consequences. It also points towards a 2-year extension period for these effects, while emphasizing that the metabolic profile improvement was partially independent from body weight loss.
The treatment of obesity with drugs that antagonize the CB1 receptors goes beyond body weight loss or merely aesthetic purposes. It is meant for high risk patients, most exhibiting excessive intra-abdominal fat associated to cardiovascular and metabolic risk factors. Actions aiming at changes in lifestyle must always be implemented. Additionally, identifying the dyslipidemic and dysglycemic phenotypes, as mentioned earlier, by measuring abdominal waist circunfrrence, may change the residual risk that is still reported by a significant number of patients.
Fig. 7 - Changes observed in HDL-c concentrations and triglycerides with the administration of rimonabant 20 mg were partially independent of weight loss. Data
from RIO-Europe. Logistic regression models were used, using weight loss as co-variable. Adapted from: Van Gaal LF et al.75
20 mg vsPlacebo
P=0.005
-14 -10 -6 -2
2
6
10
14
Total Triglycerides reduction:
-15.3 %
Total HDL-c
increase: +9.3 %
20 mg vsPlacebo
P=0.005
C
ha
ng
e
%
Triglycerides
HDL-cholesterol
Effect related to weight loss
Effect related to weight loss
-6.7% -6.7% Effect not related to
weight loss -8.6% Effet related to weight loss
Effet related to weight loss
+5.1% +5.1% Effect not related to
weight loss
+4.2%
Fig. 8 - RIO-Lipids data show plasma adiponectin levels increased over 57%
with the administration of rimonabant when compared to baseline levels.
It is relevant that over 55% of such increase was independent of weight loss. Asterisk represents P<0.01 (difference between rimonabant 20mg vs placebo). Adapted from: Després JP et al.17
0 1 2 3 4 5 6 7 8 9
A
di
po
ne
cti
n
le
ve
ls
(u
g/
m
L)
Placebo Rimonabant20 mg
1 year
Baseline
5.7 6.4
5.9 8.1 ↑57.7%
↑57.7%
↑17%
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